tbuckley/cabot-search huggingface dataset:
Patients with treated indolent lymphomas immunized with <scp>BNT162b2</scp> have reduced anti‐spike neutralizing <scp>IgG</scp> to <scp>SARS‐CoV</scp>‐2 variants, but preserved antigen‐specific T cell responses
Authors: Brendan Beaton, Sarah C. Sasson, Katherine Rankin, Juliette Raedemaeker, Alexander Wong, Priyanka Hastak, Chansavath Phetsouphanh, Andrew Warden, Vera Klemm, C. Mee Ling Munier, Alexandra Carey Hoppe, Fiona Tea, Aleha Pillay, Alberto Ospina Stella, Anupriya Aggarwal, Orly Lavee, Ian D. Caterson, Stuart Turville, Anthony D. Kelleher, Fabienne Brilot, Judith Trotman
Journal: American Journal of Hematology (2022)

Patients with indolent lymphoma undertaking recurrent or continuous B cell suppression are at risk of severe COVID-19. Patients and healthy controls (HC; N = 13) received two doses of BNT162b2: follicular lymphoma (FL; N = 35) who were treatment naïve (TN; N = 11) or received immunochemotherapy (ICT; N = 23) and Waldenström's macroglobulinemia (WM; N = 37) including TN (N = 9), ICT (N = 14), or treated with Bruton's tyrosine kinase inhibitors (BTKi; N = 12). Anti-spike immunoglobulin G (IgG) was determined by a high-sensitivity flow-cytometric assay, in addition to live-virus neutralization. Antigen-specific T cells were identified by coexpression of CD69/CD137 and CD25/CD134 on T cells. A subgroup (N = 29) were assessed for third mRNA vaccine response, including omicron neutralization. One month after second BNT162b2, median anti-spike IgG mean fluorescence intensity (MFI) in FL ICT patients (9977) was 25-fold lower than TN (245 898) and HC (228 255, p = .0002 for both). Anti-spike IgG correlated with lymphocyte count (r = .63; p = .002), and time from treatment (r = .56; p = .007), on univariate analysis, but only with lymphocyte count on multivariate analysis (p = .03). In the WM cohort, median anti-spike IgG MFI in BTKi patients (39 039) was reduced compared to TN (220 645, p = .0008) and HC (p < .0001). Anti-spike IgG correlated with neutralization of the delta variant (r = .62, p < .0001). Median neutralization titer for WM BTKi (0) was lower than HC (40, p < .0001) for early-clade and delta. All cohorts had functional T cell responses. Median anti-spike IgG decreased 4-fold from second to third dose (p = .004). Only 5 of 29 poor initial responders assessed after third vaccination demonstrated seroconversion and improvement in neutralization activity, including to the omicron variant.
Abstract 5691: Preclinical evaluation of TFX05-01, a selective AKR1C3- targeted prodrug for solid tumor
Authors: Charles Z Ding, Zhe Cai, Wei Sha
Journal: Cancer Research (2022)

Abstract Objective: Aldo-keto reductase 1C3 (AKR1C3), is a member of the aldo-keto reductase superfamily, catalyzing the NADP(H)-dependent stereospecific reduction of various aldehydes and ketones. AKR1C3 is overexpressed in a variety of cancer cells, including hepatocellular carcinoma (HCC), castration-resistant prostate cancer (CRPC), and leukemia cells. This study is to investigate the in vitro and in vivo antitumor activity of TFX05-01, a selective AKR1C3-activated anticancer prodrug, in preclinical models of AKR1C3 overexpressing cells. The studies provide solid foundation for nomination of TFX05-01 for clinical trials. Method: Enzymatic activation of TFX05-01 was investigated in vitro using recombinant human AKR1C3. Cellular anti-proliferative activity was evaluated with a range of AKR1C3 overexpressed or low expressed cell lines. The in vivo antitumor activity was evaluated in various CDX mouse models with high expression of AKR1C3, including HepG2 and castration-resistant prostate VCaP, as well as PDX leukemia models Result: TFX05-01 is a prodrug which selectively releases a DNA alkylating agent (TFX05-01A) upon exposure to AKR1C3. TFX05-01 inhibited cell proliferation in several AKR1C3 overexpressed HCC cell lines with an IC50 ≤ 100 nM. In contrast, TFX05-01 showed much lower anti-proliferative activity in low or no AKR1C3 expressed cells with an IC50 value greater than 1 μM. The cytotoxic potency of TFX05-01 in cancer cells correlates with the level of AKR1C3 expression, and the cytotoxic activity of TFX05-01 was inhibited when used in combination with a specific AKR1C3 inhibitor (IC50: 0.7 nM without inhibitor vs 188 nM with inhibitor in SNU-878 cells). TFX05-01 showed antitumor efficacy in AKR1C3 highly expressed HepG2 subcutaneously implanted xenograft model (TGI = 97% @2 mpk, QW, 3 doses IV). Concomitant PK studies showed that the concentration of active metabolites (TFX05-01A) in tumor was significantly higher (15~50 times) than that in plasma, which correlates with the selective release of the active DNA alkylating agent upon exposure to AKR1C3 in tumor tissues. Conclusion: TFX05-01 is a novel selective AKR1C3-activated prodrug, which is different from traditional non-selective alkylating agents for cancer therapy. Preclinical studies have shown profound in vivo efficacy of TFX05-01 in AKR1C3 overexpressed mouse tumor xenograft models without marked toxicity. TFX05-01 represents a novel treatment option for AKR1C3 expressing solid cancers. Preclinical GLP safety evaluations were promising and TFX05-01 was nominated for clinical trials. Citation Format: Charles Z Ding, Zhe Cai, Wei Sha. Preclinical evaluation of TFX05-01, a selective AKR1C3- targeted prodrug for solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5691.
Abstract 2989: FAP facilitates ovary tumorigenesis through the NF-κB/survivin funcational axis
Authors: Bin Li, Shuang Huang
Journal: Cancer Research (2022)

Abstract Ovarian cancer is the deadliest gynecologic cancer, mainly attributing to lack of early diagnosis of the diseases. Current mainstay treatment for ovarian cancer is surgical removal followed by chemotherapy. Although patients initially respond well, most of patients suffer from relapse and die from metastasis. Therefore, developing successful approaches combatting metastasis is most likely to prolong patients’ survival and improve their life quality. Toward this goal, we analyzed The Cancer Genome Atlas ovarian cancer patient dataset to reach for targetable genes preferentially elevated in advanced ovarian cancer. Among them, we found that knockdown of fibroblast activation protein alpha (FAP) led to dramatic apoptosis in mesenchymal-like ovarian cancer cells. To elucidate the underlying mechanism, we performed RNAseq and identified that TNF-alpha/NF-κB signaling pathway was impaired in FAP-knockdown cells. NF-κB signaling pathway is well characterized to promote cell survival by elevating the expression of pro-survival genes. In fact, the level of survivin was diminished upon FAP-knockdown. As forced expression of survivin almost completely abrogated apoptosis elicited by FAP-knockdown and survivin inhibitor also induced robust apoptosis in ovarian cancer cells, we reason that FAP participates in ovarian cancer development by promoting cell survival through activation of NF-κB/survivin axis. With the aid of EpCAM aptamer as delivering cargo, we demonstrated that FAP siRNA was able to suppress intraperitoneal ovarian cancer development. This study suggests that FAP is an ideal therapeutic target against mesenchymal-like ovarian cancer. Citation Format: Bin Li, Shuang Huang. FAP facilitates ovary tumorigenesis through the NF-κB/survivin funcational axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2989.
Risk Assessment for Hip and Knee Osteoarthritis Using Polygenic Risk Scores
Authors: Bahar Sedaghati‐Khayat, Cindy G. Boer, Jos Runhaar, Sita M. A. Bierma‐Zeinstra, Linda Broer, M. Arfan Ikram, Eleftheria Zeggini, André G. Uitterlinden, Jeroen G. J. van Rooij, Joyce B. J. van Meurs
Journal: Arthritis & Rheumatology (2022)

Objective Polygenic risk scores (PRS) allow risk stratification using common single‐nucleotide polymorphisms (SNPs), and clinical applications are currently explored for several diseases. This study was undertaken to assess the risk of hip and knee osteoarthritis (OA) using PRS. Methods We analyzed 12,732 individuals from a population‐based cohort from the Rotterdam Study (n = 11,496), a clinical cohort (Cohort Hip and Cohort Knee [CHECK] study; n = 908), and a high‐risk cohort of overweight women (Prevention of Knee OA in Overweight Females [PROOF] study; n = 328), for the association of the PRS with prevalence/incidence of radiographic OA, of clinical OA, and of total hip replacement (THR) or total knee replacement (TKR). The hip PRS and knee PRS contained 44 and 24 independent SNPs, respectively, and were derived from a recent genome‐wide association study meta‐analysis. Standardized PRS (with Z transformation) were used in all analyses. Results We found a stronger association of the PRS for clinically defined OA compared to radiographic OA phenotypes, and we observed the highest PRS risk stratification for TKR/THR. The odds ratio (OR) per SD was 1.3 for incident THR (95% confidence interval [95% CI] 1.1–1.5) and 1.6 (95% CI 1.3–1.9) for incident TKR in the Rotterdam Study. The knee PRS was associated with incident clinical knee OA in the CHECK study (OR 1.3 [95% CI 1.1–1.5]), but not for the PROOF study (OR 1.2 [95% CI 0.8–1.7]). The OR for OA increased gradually across the PRS distribution, up to 2.1 (95% CI 1.4–3.2) for individuals with the 10% highest PRS compared to the middle 50% of the PRS distribution. Conclusion Our findings validated the association of PRS across OA definitions. Since OA is becoming frequent and primary prevention is not commonly applicable, PRS‐based risk assessment could play a role in OA prevention. However, the utility of PRS is dependent on the setting. Further studies are needed to test the integration of genetic risk assessment in diverse health care settings.
Abstract 2328: Metabolomics pathways and biomarkers in predicting breast cancer prognosis
Authors: Jennifer J. Hu, Cristiane Takita, Isildinha M. Reis, George Yang, Wei Zhao, Eunkyung Lee
Journal: Cancer Research (2022)

Abstract Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in Americans. With more than 3 million breast cancer survivors in the US, a number that is projected to increase, it is important to identify targets for precision intervention to improve breast cancer prognosis. With the rapid advancement of technology for metabolomics, the results from several recent studies have shown that metabolomics may have applications in breast cancer diagnosis and subtype analysis, characterization of heterogeneity of breast cancer, and prognosis. In the current study, we performed a global urinary metabolomic analysis of 120 breast cancer patients: 60 progression-free (PF) cases as the reference group and 60 with progressive disease (PD: recurrence, second primary, metastasis, or death). The urine samples were collected immediately after radiotherapy. Using UPLC-MS/MS and GC-MS, Metabolon Inc. identified a robust set of 1,742 biochemicals (1,258 known and 484 unknown structure). The most notable differences between PF and PD patients involved multiple pathways and metabolites include: carbohydrate metabolism (e.g., glucose, sedoheptulose, and N6-carboxymethyllysine), branch-chain amino acid metabolism (e.g., alpha-hydroxyisocaproate and beta-hydroxyisovalerylglycine), phosphatidylcholine metabolism (e.g., 1-palmitoyl-2-oleoyl-GPC (16:0/18:1) and 1-palmitoyl-2-linoleoyl-GPC (16:0/18:2)), arginine metabolism (e.g., dimethylarginine, N-acetylcitrulline, and homocitrulline), oxidative stress-related metabolites (e.g., cysteine-glutathione disulfide, gamma-glutamylisoleucine, and gamma-glutamylthreonine), androgenic steroids (Dehydroepiandrosterone sulfate (DHEA-S) and 16a-hydroxy DHEA 3-sulfate), and nucleotide metabolism. Some of these identified metabolomic differences may serve as potential predictive biomarkers of breast cancer prognosis. In summary, with increasing interest in targeting tumor metabolism in precision medicine and our pilot data suggesting multiple metabolic pathways in predicting breast cancer prognosis, future research is warranted to validate our findings and identify metabolomic targets for precision interventions. Citation Format: Jennifer J. Hu, Cristiane Takita, Isildinha M. Reis, George Yang, Wei Zhao, Eunkyung Lee. Metabolomics pathways and biomarkers in predicting breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2328.
Sacubitril/valsartan use patterns among older adults with heart failure in clinical practice: a <scp>population‐based</scp> cohort study of &gt;25 000 Medicare beneficiaries
Authors: Ankeet S. Bhatt, Muthiah Vaduganathan, Scott D. Solomon, Sebastian Schneeweiss, Julie C. Lauffenburger, Rishi J. Desai
Journal: European Journal of Heart Failure (2022)
Abstract LB539: Development of GB2102, a novel and highly differentiated anti-FGFR2b antibody for the treatment of gastric cancer
Authors: Tiantian Zhou, Qinglin Du, Xueyan Yang, Fei Peng, James Li, Shuhua Han
Journal: Cancer Research (2022)

Abstract Background: Gastric cancer (GC) is a complex and heterogeneous disease with limited available treatment options. Fibroblast growth factor receptor-2b (FGFR2b) is overexpressed in approximately 2-30% of GC and associated with worse prognosis. Bemarituzumab is an afucosylated humanized monoclonal antibody that specifically inhibits FGFR2b. In the FIGHT trial, bemarituzumab showed beneficial response in GC, but appeared to cause high corneal adverse events. It was hypothesized that FGF10 inhibition may be the mechanism of corneal toxicity by bemarituzumab. We have recently generated a monoclonal antibody against FGFR2b with potent FGF7 blocking activity but weak inhibition activity for FGF10. Thus, GB2102 may represent a differentiated antibody therapeutics that has a potential to decrease the adverse effects in the eyes. Methods: GB2102 was generated by immunization of FGFR2b protein in mice followed by hybridoma technique. FGF7 and FGF10 ligand blocking was assessed by ELISA. FGF7-induced FGFR2b phosphorylation and cell proliferation were studied in SNU-16 gastric cancer tumor cell line. Antibody-dependent cell-mediated cytotoxicity (ADCC) function was evaluated by IL-2-activated NK cell-induced lysis of target cells. Results: GB2102 displayed potent blocking of FGF7-FGFR2b pathway by inhibition of FGF7-induced FGFR2b phosphorylation and tumor cell proliferation. But GB2102 showed weak blocking of FGF10 binding to FGFR2b compared with benchmark, suggesting that GB2102 may have better safety profile in corneal toxicity. In ADCC function assay, GB2102 induced potent ADCC effects by primary human NK cells to kill FGFR2b-expressing tumor cells. Conclusions: In summary, preclinical studies showed that GB2102 is an anti-FGFR2b antibody with potent ADCC effect and strong FGF7 blocking but weak FGF10 inhibition. These results suggest that GB2102 is potentially a safe and effective candidate for the treatment of FGFR2b positive gastric cancer. Citation Format: Tiantian Zhou, Qinglin Du, Xueyan Yang, Fei Peng, James Li, Shuhua Han. Development of GB2102, a novel and highly differentiated anti-FGFR2b antibody for the treatment of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB539.
Abstract CT250: A first-in-human phase 1 study of NL-201 in patients with relapsed or refractory cancer
Authors: Aung Naing, Margaret Callahan, Brian A. Costello, Brendan Curti, Evan Hall, Aaron Hansen, Georgina V. Long, Anthony M. Joshua, Cynthia Wetmore, Andrew Weickhardt
Journal: Cancer Research (2022)

Abstract Background: NL-201 is a selective and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors, which share beta and gamma signaling subunits. NL-201 is being developed as a potent activator of CD8+ T cells and NK cells for cancer immunotherapy. Binding to the beta and gamma subunits stimulates dose-dependent expansion and tumor infiltration of cytotoxic CD8+ T cells and NK cells, thereby enhancing the immune response in the tumor. The absence of binding to the IL-2 alpha subunit reduces the undesirable effects of traditional IL-2 therapies, such as vascular leak syndrome and expansion of immunosuppressive regulatory T cells. As such, NL-201 is designed to promote the desired immunomodulatory anti-tumor effects of IL-2 with an improved safety profile. Methods: NL201-101 is a Phase 1 first-in-human, open-label, dose-escalation and cohort expansion study consisting of two parts. Part 1 is a monotherapy dose-escalation study in up to 60 adult patients with advanced and/or refractory solid tumors to define the safety profile and the recommended Phase 2 dose (RP2D) and schedule of NL-201. During dose escalation, two different schedules will be evaluated: dosing every 21 days (Schedule A), or on days 1 and 8 of each 21-day cycle (Schedule B). Tumor response will be assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and/or RECIST for use in cancer immunotherapy trials (iRECIST). In Part 2, patients with pathologically proven diagnosis of melanoma and renal cell carcinoma (up to N=30/cohort), who have advanced and/or refractory measurable disease and have failed at least one line of treatment, which may include checkpoint inhibitors, will be enrolled. Key exclusion criteria include history of brain cancer or active brain metastases, carcinomatous meningitis, neurologic autoimmune disease; patients previously receiving CAR-T or IL-2-based therapies are not eligible. Recruitment of Part 1 began in April 2021, and the trial is actively enrolling. Clinicaltrials.gov identifier: NCT04659629. Citation Format: Aung Naing, Margaret Callahan, Brian A. Costello, Brendan Curti, Evan Hall, Aaron Hansen, Georgina V. Long, Anthony M. Joshua, Cynthia Wetmore, Andrew Weickhardt. A first-in-human phase 1 study of NL-201 in patients with relapsed or refractory cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT250.
Abstract 6069: HOXA9 overexpression contributes to stem cell overpopulation that drives development and growth of colorectal cancer
Authors: Brian T. Osmond, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2022)

Abstract HOX genes encode master regulatory transcription factors that regulate stem cells (SCs), but their role in carcinogenesis is not fully understood. SC overpopulation drives colorectal cancer (CRC) development, which is also linked with the aberrant expression of specific HOX genes. One such gene is HOXA9. Our goal is to find out how HOXA9-regulatory mechanisms play a role in the SC origin of CRC. Previous research in our lab reported that HOXA9 as well as other HOX proteins (e.g. HOXA4 &amp; HOXD10) are selectively expressed in human colonic cancer SCs (CSCs). The SC marker aldehyde dehydrogenase (ALDH) and other retinoic acid (RA) pathway components are also selectively expressed in CSCs. Moreover, HOXA9 expression is positively correlated with expression of ALDH genes such as ALDH1A1. These findings suggest that RA signaling regulates HOXA9 gene expression in colonic ALDH+ SCs. Hypothesis: Dysregulated HOXA9 expression leads to ALDH+ SC overpopulation, which contributes to CRC growth and development. We used immunofluorescent (IF) mapping to determine the histologic location of HOXA9+ cells in relation to colonic SCs and other differentiated colonic cell types in normal and neoplastic human colonic tissues. We also measured the effects of all-trans retinoic acid (ATRA) and the ALDH enzyme inhibitor diethylamino benzaldehyde (DEAB) on HOXA9 expression, cell proliferation and differentiation using CRC cell lines. Immunofluorescence mapping indicated that not only is HOXA9 selectively expressed in ALDH-positive SCs, but that HOXA9 expression is increased in colon carcinoma tissue compared to normal colon epithelium. Our results also showed that both ATRA and DEAB treatment decreased the proliferation of HT29 and SW480 CRC cell lines. Western blot analysis showed that HOXA9 has reduced expression in ATRA-treated HT29 CRC cells. Additionally, our independent bioinformatics analyses show that HOXA9 is predominantly expressed in both stem cells and neuroendocrine cells (NECs) in normal human colonic epithelium. Taken together, these findings indicate that regulation of HOXA9 gene expression by RA signaling controls differentiation of ALDH+ SCs along the NEC lineage in human colon tissue. Thus, our results show that HOXA9 is regulated by RA signaling and when dysregulated, contributes to CRC development and growth. These findings provide a mechanism that may be targeted in the design of novel treatments against SC overpopulation in CRC. Citation Format: Brian T. Osmond, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. HOXA9 overexpression contributes to stem cell overpopulation that drives development and growth of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6069.
Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits
Authors: Carly E. Whyte, Kailash Singh, Oliver T. Burton, Meryem Aloulou, Lubna Kouser, Rafael Valente Veiga, Amy Dashwood, Hanneke Okkenhaug, Samira Benadda, Alena Moudra, Orian Bricard, Stephanie Lienart, Pascal Bielefeld, Carlos P. Roca, Francisco José Naranjo-Galindo, Félix Lombard-Vadnais, Steffie Junius, David Bending, Masahiro Ono, Tino Hochepied, Timotheus Y.F. Halim, Susan Schlenner, Sylvie Lesage, James Dooley, Adrian Liston
Journal: The Journal of Experimental Medicine (2022)

Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5–mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.
Adolescents and young adults with rhabdomyosarcoma treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) protocols: a cohort study
Authors: Andrea Ferrari, Julia C Chisholm, Meriel Jenney, Veronique Minard-Colin, Daniel Orbach, Michela Casanova, Gabriela Guillen, Heidi Glosli, Rick R van Rijn, Reineke A Schoot, Alison L Cameron, Timothy Rogers, Rita Alaggio, Myriam Ben-Arush, Henry C Mandeville, Christine Devalck, Anne-Sophie Defachelles, Beatrice Coppadoro, Gianni Bisogno, Johannes H M Merks
Journal: The Lancet Child & Adolescent Health (2022)